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Naked DNA Rejuvenates Rheumatoid Rodents

Date:

June 18, 1998

Source:

NIH-National Institute Of Dental Research

Summary:

Scientists have unveiled a stripped-down form of gene therapy to treat arthritis in an experimental animal model. Naked DNA, unencumbered by the standard assortment of gene carriers, was effective when injected directly into muscle tissue.

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Scientists have unveiled a stripped-down form of gene therapy to treat arthritis in an experimental animal model. Naked DNA, unencumbered by the standard assortment of gene carriers, was effective when injected directly into muscle tissue. Remarkably, this straightforward procedure dramatically reduced chronic arthritis symptoms in the joints, and now offers an innovative approach for eventually treating human disease. The results of the study, carried out at the National Institutes of Health, appear in the June 15 issue of The Journal of Clinical Investigation.

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The naked DNA at the center of the scientific spotlight consists of a double-stranded circle of nucleotide bases, known as a plasmid. This particular plasmid contains the genetic code for human transforming growth factor-beta (TGF-ί), a protein that is a key regulator of inflammation-the body's response to infection or tissue damage.

Drs. Xaio-yu Song and Sharon Wahl from the National Institute of Dental Research (NIDR), and MiLi Gu from the Food and Drug Administration (FDA) tested the TGF-ί plasmid in a rat model for human rheumatoid arthritis. In this model, animals that are injected in the abdomen with a preparation of bacterial cell walls soon develop swollen and inflamed joints in the feet. The acute arthritic phase lasts several days and then develops into a long-term chronic condition that is marked by the erosion of cartilage and bone within the joints. When the scientists injected TGF-ί plasmids into muscle tissue, they noticed a dramatic reduction in disease symptoms in the joints. The number of affected joints and the amount of swelling in the joints were both substantially reduced.

Although injection of plasmids prior to initiating arthritis with bacterial cell walls did not prevent the onset of disease, injections timed at different periods after symptoms began alleviated conditions in the later occurring chronic phase. Inflammation was greatly reduced and essentially no cartilage or bone destruction occurred. Not only does the procedure avoid the invasion of painful joints, but also a single injection into muscle suppressed arthritis symptoms for up to three months after treatment.

The use of TGF-ί plasmids to treat arthritis evolved from previous work by Dr. Wahl, director of NIDR's Oral Infection and Immunity Branch. These earlier studies, which used the TGF-ί protein rather than the gene-containing plasmid, showed that TGF-ί could protect rats from arthritic joint destruction. However, it soon became apparent that the manner in which the protein was administered to the animals determined whether or not the outcome was favorable.

Injecting TGF-ί directly into joints led to a worsening of the condition. On the other hand, injection into the abdomen or under the skin, which delivers TGF-ί into the blood stream, dramatically improved symptoms. The investigators felt that TGF-ί may exert its effects indirectly through cells that lie outside of the joint itself. However, this route of delivery also carries the risk of bone marrow suppression, anemia, and formation of fibrous tissues in the kidneys--undesirable side effects associated with exposing the entire body to high levels of TGF-ί.

It was clear to Drs. Song and Wahl that using the TGF-ί gene rather than the protein might be the best way to get the right amount of TGF-ί into the body and ultimately deliver its positive effects to the joints. The plasmid gene could produce a low-level supply of TGF-ί that could do its work on the joints without disrupting the delicate balance of other bodily functions. Yet, standard methods of gene therapy are also fraught with difficulties.

The gene must somehow be incorporated into the host cells. This is usually accomplished by packaging DNA into a viral vector that infects the host cells, carrying with it the desired gene. Such gene transfers are usually transient, and repeated attempts are short-circuited when the immune system recognizes and destroys the invading virus. Vector-induced inflammation of host tissues is also a common occurrence.

Recent work by several research groups has pointed to naked DNA in plasmid form as a way to circumvent some of the problems associated with conventional gene therapy. Plasmids don't induce inflammation or elicit an immune response, and initial results in animals have been encouraging. Plasmids injected directly into tissue have been used to tackle animal models for cancer and muscular dystrophy. Also, recent work with TGF-ί plasmids has produced promising results in animal models for the inflammatory disorders, lupus and colitis.

Dr. Wahl felt that a similar approach might be an excellent way to treat arthritis in the experimental animals, and the initial success of this study lays the groundwork for further testing and clinical development. Working with Drs. Song, Gu, and Wahl on the study were Wen-wen Jin from NIDR and Dr. Dennis Klinman from the FDA's Center for Biologic Evaluation and Research.

The NIDR, one of the National Institutes of Health (NIH) located in Bethesda, Maryland, is the nation's leading supporter of research in dental, oral, and craniofacial health. The FDA is a sister agency to NIH within the Department of Health and Human Services.

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